title: A novel bispecific EGFR/Met antibody blocks tumor-promoting phenotypic effects induced by resistance to EGFR inhibition and has potent antitumor activity.
abstract: Simultaneous targeting of epidermal growth factor receptor (EGFR) and Met in cancer therapy is under pre-clinical and clinical evaluation. Here, we report the finding that treatment with EGFR inhibitors of various tumor cells, when stimulated with hepatocyte growth factor (HGF) and EGF, results in transient upregulation of phosphorylated AKT. Furthermore, EGFR inhibition in this setting stimulates a pro-invasive phenotype as assessed in Matrigel-based assays. Simultaneous treatment with AKT and EGFR inhibitors abrogates this invasive growth, hence functionally linking signaling and phenotype. This observation implies that during treatment of tumors a balanced ratio of EGFR and Met inhibition is required. To address this, we designed a bispecific antibody targeting EGFR and Met, which has the advantage of a fixed 2:1 stoichiometry. This bispecific antibody inhibits proliferation in tumor cell cultures and co-cultures with fibroblasts in an additive manner compared with treatment with both single agents. In addition, cell migration assays reveal a higher potency of the bispecific antibody in comparison with the antibodies' combination at low doses. We demonstrate that the bispecific antibody inhibits invasive growth, which is specifically observed with cetuximab. Finally, the bispecific antibody potently inhibits tumor growth in a non-small cell lung cancer xenograft model bearing a strong autocrine HGF-loop. Together, our findings strongly support a combination treatment of EGFR and Met inhibitors and further evaluation of resistance mechanisms to EGFR inhibition in the context of active Met signaling.
authors.affiliation: Pharma Research and Early Development (pRED), Roche Diagnostics GmbH, Penzberg, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Castoldi
authors.affiliation: Pharma Research and Early Development (pRED), Roche Diagnostics GmbH, Penzberg, Germany.
authors.forename: V
authors.initials: V
authors.lastname: Ecker
authors.affiliation: Pharma Research and Early Development (pRED), Roche Diagnostics GmbH, Penzberg, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Wiehle
authors.affiliation: Pharma Research and Early Development (pRED), Roche Diagnostics GmbH, Penzberg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Majety
authors.affiliation: Pharma Research and Early Development (pRED), Roche Diagnostics GmbH, Penzberg, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Busl-Schuller
authors.affiliation: Pharma Research and Early Development (pRED), Roche Diagnostics GmbH, Penzberg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Asmussen
authors.affiliation: Pharma Research and Early Development (pRED), Roche Diagnostics GmbH, Penzberg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Nopora
authors.affiliation: Pharma Research and Early Development (pRED), Roche Diagnostics GmbH, Penzberg, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Jucknischke
authors.affiliation: Pharma Research and Early Development (pRED), Roche Diagnostics GmbH, Penzberg, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Osl
authors.affiliation: Division of Clinical Pharmacology, Department of Internal Medicine IV, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Kobold
authors.affiliation: Pharma Research and Early Development (pRED), Roche Diagnostics GmbH, Penzberg, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Scheuer
authors.affiliation: Pharma Research and Early Development (pRED), Roche Diagnostics GmbH, Penzberg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Venturi
authors.affiliation: pRED, Roche Glycart AG, Schlieren, Switzerland.
authors.forename: C
authors.initials: C
authors.lastname: Klein
authors.affiliation: Pharma Research and Early Development (pRED), Roche Diagnostics GmbH, Penzberg, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Niederfellner
authors.affiliation: Pharma Research and Early Development (pRED), Roche Diagnostics GmbH, Penzberg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Sustmann
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D051379:Mice; D010641:Phenotype; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D018033:Antibodies, Bispecific; D000970:Antineoplastic Agents; D017228:Hepatocyte Growth Factor; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met; D051057:Proto-Oncogene Proteins c-akt